Protein-protein Interactions (PPIs) play critical roles in biological processes that can propagate or terminate llfe.These PPIs have been Implicated In numerous disease states, including HIV, diabetes, and cardiovascular and neurodegenerative diseases, making them Important targets for dIsruptlon.Often recognition between proteins is mediated by protein secondary structures, such as a-helices, via one helical face, where interacting residues occupy predominantly the /, / + 3 or / + 4, and / + 7 positions. Accordingly, these surfaces are critical targets for small molecule mimicry. Our previous focus has yielded a-helix mimetics with Inherent disadvantages, either poor solubility (terphenyl and terpyridine scaffolds) or hydrogen-bonding networks to maintain their correct orientation (terephthalamide and thspyrldylamlde scaffolds). As a mechanism to overcome the disadvantages of our previous designs, we have reported an Innovative scaffold that replaces the terminal six-membered aromatic end units with water-soluble five-membered heterocyclic groups.